While the renal and central nervous system manifestations of systemic lupus erythematosus (SLE) often present as compelling indications for aggressive cytotoxic therapy, recent data demonstrate that a significant proportion of those patients have asymptomatic cardiovascular disease (CVD) that goes unrecognized and can eventually result in important morbidity and mortality. Our center has performed a major case-control study to document the prevalence of premature atherosclerosis among patients with SLE and is extending that study to patients with rheumatoid arthritis (RA). Although SLE patients and controls were comparable in CVD risk factors, atherosclerosis (carotid plaque) was more prevalent in SLE patients (37 vs. 15%, p<0.001). To elucidate the underlying mechanisms that account for premature atherosclerosis in these patients, a panel of proinflammatory mediators in peripheral blood was assessed. The data were unrevealing of relevant mechanisms, as SLE patients either with or without carotid plaque expressed elevated levels of cytokines, soluble adhesion molecules, and soluble CD154. However, important clues regarding potential disease mechanisms were revealed based on analysis of microarray data from a subset of the SLE study subjects. The data have stimulated the hypothesis that activation of the platelet-monocyte-endothelial cell axis contributes to premature atherosclerosis in SLE. Preliminary data suggest that specific gene products that may be important mediators of vascular damage are increased in expression in SLE patients with carotid plaque. The proposed research will investigate the expression of these vascular mediators in our cohort of SLE and RA patients characterized for carotid disease and will study the functional relationship among the cells that express these factors. The specific aims are: 1) to investigate the expression of CD154 in rheumatic disease patients with premature atherosclerosis; 2) to investigate the expression of potential biomarkers of vascular disease in rheumatic disease patients with premature atherosclerosis; and 3) to determine the role of platelets and monocytes in generating pro-atherogenic mediators. Early identification of biomarkers in those patients who will go on to develop premature atherosclerotic disease and institution of biomarkers in those patients who will go on to develop premature atherosclerotic disease and institution of appropriate therapy should have a major impact on patient health and survival.